tbuckley/cabot-search huggingface dataset:
Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials
Authors: Gil Yosipovitch, Nicholas Mollanazar, Sonja Ständer, Shawn G. Kwatra, Brian S. Kim, Elizabeth Laws, Leda P. Mannent, Nikhil Amin, Bolanle Akinlade, Heribert W. Staudinger, Naimish Patel, George D. Yancopoulos, David M. Weinreich, Sheldon Wang, Genming Shi, Ashish Bansal, John T. O’Malley
Journal: Nature Medicine (2023)

Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, measured by proportion of patients with a ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included nodule number reduction to ≤5 at week 24. PRIME and PRIME2 enrolled 151 and 160 patients, respectively. Both trials met all the pre-specified primary and key secondary endpoints. A ≥4-point WI-NRS reduction at week 24 in the dupilumab and placebo arms was achieved by 60.0% and 18.4% of patients, respectively, in PRIME (95% confidence interval (CI), 27.8-57.7 for the difference, P < 0.001) and at week 12 by 37.2% and 22.0% of patients, respectively, in PRIME2 (95% CI, 2.3-31.2; P = 0.022). Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions versus placebo in PN. Safety was consistent with the known dupilumab safety profile.ClinicalTrials.gov identifiers: NCT04183335 and NCT04202679 .
Predicting Environmental and Ecological Drivers of Human Population Structure
Authors: Evlyn Pless, Anders M Eckburg, Brenna M Henn
Journal: Molecular Biology and Evolution (2023)

Landscape, climate, and culture can all structure human populations, but few existing methods are designed to simultaneously disentangle among a large number of variables in explaining genetic patterns. We developed a machine learning method for identifying the variables which best explain migration rates, as measured by the coalescent-based program MAPS that uses shared identical by descent tracts to infer spatial migration across a region of interest. We applied our method to 30 human populations in eastern Africa with high-density single nucleotide polymorphism array data. The remarkable diversity of ethnicities, languages, and environments in this region offers a unique opportunity to explore the variables that shape migration and genetic structure. We explored more than 20 spatial variables relating to landscape, climate, and presence of tsetse flies. The full model explained ∼40% of the variance in migration rate over the past 56 generations. Precipitation, minimum temperature of the coldest month, and elevation were the variables with the highest impact. Among the three groups of tsetse flies, the most impactful was fusca which transmits livestock trypanosomiasis. We also tested for adaptation to high elevation among Ethiopian populations. We did not identify well-known genes related to high elevation, but we did find signatures of positive selection related to metabolism and disease. We conclude that the environment has influenced the migration and adaptation of human populations in eastern Africa; the remaining variance in structure is likely due in part to cultural or other factors not captured in our model.
Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial
Authors: Jason A Chesney, Igor Puzanov, Frances A Collichio, Parminder Singh, Mohammed M Milhem, John Glaspy, Omid Hamid, Merrick Ross, Philip Friedlander, Claus Garbe, Theodore Logan, Axel Hauschild, Celeste Lebbé, Harshada Joshi, Wendy Snyder, Janice M Mehnert
Journal: Journal for ImmunoTherapy of Cancer (2023)

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 106 plaque-forming units (PFU)/mL in week 1, followed by 108 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported.At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297.
Validation of a microRNA liquid biopsy assay for diagnosis and risk stratification of invasive cutaneous melanoma
Authors: Ryan Van Laar, Babak Latif, Sam King, Christopher Love, Nadine Taubenheim, Esha Kalansooriya, Wandi Wang, Mirette Saad, Ingrid Winship, Anthony Azzi, Alister Lilleyman, Tony Landgren
Journal: British Journal of Dermatology (2023)

Abstract Background Noninvasive molecular biomarkers are needed to improve the early, accurate and precise diagnosis of invasive cutaneous melanoma. Objectives To independently validate a previously identified circulating microRNA signature of melanoma (MEL38), and, secondly, to develop a complementary microRNA signature, optimized for prognostication. Patients and Methods MicroRNA expression profiling was performed on plasma samples from a multicentre observational case–control study, involving patients with primary or metastatic melanoma, melanoma in situ, nonmelanoma skin cancer, or benign naevi. MicroRNA profiles from patients with length of survival, treatment and sentinel lymph node biopsy (SLNB) data were used to develop the prognostic signature. The primary outcome of interest for MEL38 was its association with melanoma status, including area under the curve, binary diagnostic sensitivity and specificity, and incidence-adjusted positive and negative predictive values. The prognostic signature was assessed using rates of survival per risk group and relationship to conventional predictors of outcome. Results Circulating microRNA profiles of 372 patients with invasive melanoma and 210 control individuals were generated. The average age of all participants was 59 years; 49% were male. A MEL38 score &amp;gt; 5.5 indicated the presence of invasive melanoma. Overall, 551/582 (95%) of patients were correctly diagnosed, with 93% sensitivity and 98% specificity. MEL38 score ranged from 0 to 10 with an area under the curve of 0.98 (95% confidence interval 0.97–0.99, P &amp;lt; 0.001). A novel prognostic 12-microRNA signature (MEL12) developed from 232 patients identified low-, standard- or high-risk groups, with 94%, 78% and 58% rates of 10-year melanoma-specific survival, respectively (log-rank P &amp;lt; 0.001). MEL12 prognostic risk groups were significantly associated with clinical staging (χ2, P &amp;lt; 0.001) and SLNB status (P = 0.027). Patients who were classified as high risk by MEL12 were approximately three times more likely to have melanoma detected in their sentinel lymph nodes compared to low-risk patients. Conclusions The circulating MEL38 signature may assist in diagnosing patients with invasive melanoma vs. other conditions associated with a lower – or negligible – risk of mortality. A complementary and prognostic MEL12 signature is predictive of SLNB status, clinical stage and probability of survival. Plasma microRNA profiling may help to optimize existing diagnostic pathways as well as enable personalized, risk-informed melanoma treatment decisions.
Short-term Adverse Events Following Immunization With Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) Vaccine for Mpox
Authors: Lucy Deng, Laura K. Lopez, Catherine Glover, Patrick Cashman, Renee Reynolds, Kristine Macartney, Nicholas Wood
Journal: JAMA (2023)

This study uses data collected by Australia’s vaccine safety surveillance system to examine the adverse event profile of the modified vaccinia Ankara–Bavarian Nordic vaccine.
Elimination of methicillin-resistant Staphylococcus aureus biofilms on titanium implants via photothermally-triggered nitric oxide and immunotherapy for enhanced osseointegration
Authors: Yong-Lin Yu, Jun-Jie Wu, Chuan-Chuan Lin, Xian Qin, Franklin R. Tay, Li Miao, Bai-Long Tao, Yang Jiao
Journal: Military Medical Research (2023)

Treatment of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium (Ti) implants. There is a need to explore more effective approaches for the treatment of MRSA biofilm infections.Herein, an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles (PDA), nitric oxide (NO) release donor sodium nitroprusside (SNP) and osteogenic growth peptide (OGP) onto Ti implants, denoted as Ti-PDA@SNP-OGP. The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy, X-ray photoelectron spectroscope, water contact angle, photothermal property and NO release behavior. The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2',7'-dichlorofluorescein diacetate probe, 1-N-phenylnaphthylamine assay, adenosine triphosphate intensity, o-nitrophenyl-β-D-galactopyranoside hydrolysis activity, bicinchoninic acid leakage. Fluorescence staining, assays for alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization, quantitative real‑time reverse transcription‑polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells (MSCs), RAW264.7 cells and their co-culture system. Giemsa staining, ELISA, micro-CT, hematoxylin and eosin, Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms, inhibition of inflammatory response, and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo.Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light irradiation, and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species (ROS)-mediated oxidative stress, destroying bacterial membrane integrity and causing leakage of intracellular components (P < 0.01). In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs, but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype (P < 0.05 or P < 0.01). The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways (P < 0.01). In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model (P < 0.01).These findings suggest that Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.
NUP98::Nsd1 and FLT3-ITD collaborate to generate acute myeloid leukemia
Authors: Toshihiro Matsukawa, Mianmian Yin, Nupur Nigam, Vijay Negi, Li Li, Donald Small, Yuelin J. Zhu, Robert L. Walker, Paul S. Meltzer, Peter D. Aplan
Journal: Leukemia (2023)
Relationship among three common hematological premalignant conditions
Authors: Nicholas J Boddicker, Sameer A Parikh, Aaron D Norman, Kari G Rabe, Rosalie Griffin, Timothy G Call, Dennis P Robinson, Janet E Olson, Angela Dispenzieri, Vincent Rajkumar, Shaji Kumar, Neil E Kay, Curtis A Hanson, James R Cerhan, David Murray, Esteban Braggio, Tait D Shanafelt, Celine M Vachon, Susan L Slager
Journal: Leukemia (2023)
Detection of viral RNAs at ambient temperature via reporter proteins produced through the target-splinted ligation of DNA probes
Authors: Elizabeth A. Phillips, Adam D. Silverman, Aric Joneja, Michael Liu, Carl Brown, Paul Carlson, Christine Coticchia, Kristen Shytle, Alex Larsen, Nadish Goyal, Vincent Cai, Jason Huang, Jennifer E. Hickey, Emily Ryan, Joycelynn Acheampong, Pradeep Ramesh, James J. Collins, William J. Blake
Journal: Nature Biomedical Engineering (2023)

Abstract Nucleic acid assays are not typically deployable in point-of-care settings because they require costly and sophisticated equipment for the control of the reaction temperature and for the detection of the signal. Here we report an instrument-free assay for the accurate and multiplexed detection of nucleic acids at ambient temperature. The assay, which we named INSPECTR (for internal splint-pairing expression-cassette translation reaction), leverages the target-specific splinted ligation of DNA probes to generate expression cassettes that can be flexibly designed for the cell-free synthesis of reporter proteins, with enzymatic reporters allowing for a linear detection range spanning four orders of magnitude and peptide reporters (which can be mapped to unique targets) enabling highly multiplexed visual detection. We used INSPECTR to detect a panel of five respiratory viral targets in a single reaction via a lateral-flow readout and ~4,000 copies of viral RNA via additional ambient-temperature rolling circle amplification of the expression cassette. Leveraging synthetic biology to simplify workflows for nucleic acid diagnostics may facilitate their broader applicability at the point of care.
Modeling group heteroscedasticity in single-cell RNA-seq pseudo-bulk data
Authors: Yue You, Xueyi Dong, Yong Kiat Wee, Mhairi J Maxwell, Monther Alhamdoosh, Gordon K Smyth, Peter F Hickey, Matthew E Ritchie, Charity W Law
Journal: Genome biology (2023)

Group heteroscedasticity is commonly observed in pseudo-bulk single-cell RNA-seq datasets and its presence can hamper the detection of differentially expressed genes. Since most bulk RNA-seq methods assume equal group variances, we introduce two new approaches that account for heteroscedastic groups, namely voomByGroup and voomWithQualityWeights using a blocked design (voomQWB). Compared to current gold-standard methods that do not account for group heteroscedasticity, we show results from simulations and various experiments that demonstrate the superior performance of voomByGroup and voomQWB in terms of error control and power when group variances in pseudo-bulk single-cell RNA-seq data are unequal.
Reply: Epidemiological cut-off values for a 96-well broth microdilution plate for high-throughput research antibiotic susceptibility testing of<i>M. tuberculosis</i>
Journal: European Respiratory Journal (2023)

<b>The recent publication by the @crypticproject proposing ECOFF/ECVs for research attracted two letters to the editor. Here is the response from the CRyPTIC Consortium to both.</b>https://bit.ly/40vRLye
Reduction of<i>Paraoxonase</i>Expression Followed by Inactivation across Independent Semiaquatic Mammals Suggests Stepwise Path to Pseudogenization
Authors: Allie M Graham, Jerrica M Jamison, Marisol Bustos, Charlotte Cournoyer, Alexa Michaels, Jason S Presnell, Rebecca Richter, Daniel E Crocker, Ari Fustukjian, Margaret E Hunter, Lorrie D Rea, Judit Marsillach, Clement E Furlong, Wynn K Meyer, Nathan L Clark
Journal: Molecular Biology and Evolution (2023)

Abstract Convergent adaptation to the same environment by multiple lineages frequently involves rapid evolutionary change at the same genes, implicating these genes as important for environmental adaptation. Such adaptive molecular changes may yield either change or loss of protein function; loss of function can eliminate newly deleterious proteins or reduce energy necessary for protein production. We previously found a striking case of recurrent pseudogenization of the Paraoxonase 1 (Pon1) gene among aquatic mammal lineages—Pon1 became a pseudogene with genetic lesions, such as stop codons and frameshifts, at least four times independently in aquatic and semiaquatic mammals. Here, we assess the landscape and pace of pseudogenization by studying Pon1 sequences, expression levels, and enzymatic activity across four aquatic and semiaquatic mammal lineages: pinnipeds, cetaceans, otters, and beavers. We observe in beavers and pinnipeds an unexpected reduction in expression of Pon3, a paralog with similar expression patterns but different substrate preferences. Ultimately, in all lineages with aquatic/semiaquatic members, we find that preceding any coding-level pseudogenization events in Pon1, there is a drastic decrease in expression, followed by relaxed selection, thus allowing accumulation of disrupting mutations. The recurrent loss of Pon1 function in aquatic/semiaquatic lineages is consistent with a benefit to Pon1 functional loss in aquatic environments. Accordingly, we examine diving and dietary traits across pinniped species as potential driving forces of Pon1 functional loss. We find that loss is best associated with diving activity and likely results from changes in selective pressures associated with hypoxia and hypoxia-induced inflammation.
A comparison of the efficacy of Skindex-16 and Skindex-29 in dermatomyositis
Authors: Joshua Dan, Grant Sprow, Josef Concha, Jay  Patel, Nilesh Kodali, DeAnna Diaz, Thomas Vazquez, Victoria P Werth
Journal: British Journal of Dermatology (2023)

Recently, more emphasis has been placed on patient-reported outcomes in clinical trials, which has inadvertently led to an increase in respondent burden. In this study, we found that the Skindex-16 form captures patient-reported quality of life in dermatomyositis as well as the Skindex-29 form but with fewer questions. Additional questions regarding photosensitivity, body image and cosmetic use did not correlate with skin activity in dermatomyositis.
Systematic review and meta-analysis of performance of wearable artificial intelligence in detecting and predicting depression
Authors: Alaa Abd-Alrazaq, Rawan AlSaad, Farag Shuweihdi, Arfan Ahmed, Sarah Aziz, Javaid Sheikh
Journal: npj Digital Medicine (2023)

Abstract Given the limitations of traditional approaches, wearable artificial intelligence (AI) is one of the technologies that have been exploited to detect or predict depression. The current review aimed at examining the performance of wearable AI in detecting and predicting depression. The search sources in this systematic review were 8 electronic databases. Study selection, data extraction, and risk of bias assessment were carried out by two reviewers independently. The extracted results were synthesized narratively and statistically. Of the 1314 citations retrieved from the databases, 54 studies were included in this review. The pooled mean of the highest accuracy, sensitivity, specificity, and root mean square error (RMSE) was 0.89, 0.87, 0.93, and 4.55, respectively. The pooled mean of lowest accuracy, sensitivity, specificity, and RMSE was 0.70, 0.61, 0.73, and 3.76, respectively. Subgroup analyses revealed that there is a statistically significant difference in the highest accuracy, lowest accuracy, highest sensitivity, highest specificity, and lowest specificity between algorithms, and there is a statistically significant difference in the lowest sensitivity and lowest specificity between wearable devices. Wearable AI is a promising tool for depression detection and prediction although it is in its infancy and not ready for use in clinical practice. Until further research improve its performance, wearable AI should be used in conjunction with other methods for diagnosing and predicting depression. Further studies are needed to examine the performance of wearable AI based on a combination of wearable device data and neuroimaging data and to distinguish patients with depression from those with other diseases.
Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis
Authors: Anis Barmada, Jon Klein, Anjali Ramaswamy, Nina N. Brodsky, Jillian R. Jaycox, Hassan Sheikha, Kate M. Jones, Victoria Habet, Melissa Campbell, Tomokazu S. Sumida, Amy Kontorovich, Dusan Bogunovic, Carlos R. Oliveira, Jeremy Steele, E. Kevin Hall, Mario Pena-Hernandez, Valter Monteiro, Carolina Lucas, Aaron M. Ring, Saad B. Omer, Akiko Iwasaki, Inci Yildirim, Carrie L. Lucas
Journal: Science Immunology (2023)

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2-specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1β, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3